Cancer survivors' cardiorespiratory fitness often declines substantially during and following cancer treatment, and this pattern is alarming because inflammation is higher in sedentary than in active individuals. Indeed, when cardiorespiratory fitness is assessed objectively by maximal exercise testing, poorer physical fitness (VO2peak) is associated with higher inflammation. Chronic elevations in inflammation increase the risk for age- related diseases; the ability to limit initial inflammatory responses isan important homeostatic process. An immune challenge provides a useful paradigm for studying individual differences in inflammatory responses to infection or tissue injury. Accordingly, this project will use a typhoid vaccine as a peripheral immune stimulus to assess the magnitude and kinetics of a transient inflammatory response in breast cancer survivors. Inflammation-associated behavioral changes that have particular importance for breast cancer survivors will also be assessed--depressive symptoms, fatigue, pain, and cognitive problems. Our study addresses a novel question: does poorer cardiorespiratory fitness heighten the magnitude and duration of inflammatory responses to immune challenges, as well as magnifying maladaptive behavioral responses? Furthermore, biological and behavioral vulnerabilities intensify adverse responses to immune challenges. For example, both aging and depression enhance and prolong inflammatory responses to vaccines, and thus the ability of cardiorespiratory fitness to moderate age- and depression-related proinflammatory responses will also be assessed. This double-blind, randomized, crossover trial will evaluate inflammatory and behavioral responses to typhoid and placebo inoculations as a function of cardiorespiratory fitness, age, and depression in breast cancer survivors. The aims of the project are (1) to evaluate the relationships between cardiorespiratory fitness and inflammatory and behavioral responses (negative mood, fatigue, pain, and cognitive problems) to typhoid vaccine; (2) to determine the effects of age and depressive symptoms on inflammatory and behavioral responses to typhoid vaccine and placebo; and (3) to assess the ability of cardiorespiratory fitness to moderate age- and depression-related responses to typhoid vaccine. These questions are important because inflammation, a robust and reliable predictor of all-cause mortality in older adults, is one of the key candidate mechanisms for age-related decrements in physical function and disability. Individuals frequently encounter immune challenges in daily life, and the ability to minimize inflammatory responsiveness influences the total burden that infectious challenges or tissue injury place on an individual. Larger, more frequent, or more persistent inflammatory changes have negative consequences for health. If better cardiorespiratory fitness dampens or limits inflammatory responsiveness, then this study could demonstrate a new and novel mechanism through which regular exercise produces its substantial health benefits.